Fluorinated benzaldehydes

ABSTRACT

The present invention relates to fluorinated benzaldehydes, to a process for preparing them and also to the use of the fluorinated benzaldehydes for preparing active ingredients, especially in medicaments and agrochemicals.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to fluorinated benzaldehydes, to aprocess for preparing them and also to the use of the fluorinatedbenzaldehydes for preparing active ingredients, especially inmedicaments and agrochemicals.

[0003] 2. Brief Description of the Prior Art

[0004] Fluorinated benzaldehydes, for example fluorinated 2-hydroxy- and2-alkoxybenzaldehydes, are valuable starting materials for thepreparation of active ingredients in medicaments and agrochemicals.Their the fluorine or fluorinated substituents increase thelipophilicity and therefore the ability of the entire active ingredientmolecule to pass through membranes. For example, compounds such as5-fluoro-2-hydroxybenzaldehyde are suitable as the starting material forpreparing medicaments which are used for treating cardiovasculardiseases (see also WO-A 01/19780, p.81).

[0005] Of particular concern here are the methods of preparingfluorinated benzaldehydes and the attendant disadvantages are describedas follows. Illustratively, 5-fluoro-2-hydroxybenzaldehyde can beprepared, for example, by formylating 4-fluorophenol (Suzuki et al.,Chem. Pharm. Bull. 1963, 31(5), 1751-1753). However, the yields at lessthan 20% of theory are not acceptable.

[0006] There is therefore a need to provide fluorinated2-hydroxy-3-methylbenzaldehydes and an efficient process for thepreparation thereof..

SUMMARY OF THE INVENTION

[0007] A process has now been found for preparing compounds of theformula (I)

[0008] where

[0009] R¹ is in each case independently C₁-C₁₂-alkyl, chlorine orbromine or a radical of the formulae (IIa) or (IIb)

A-B-D-E   (IIa)

A-E   (IIb)

[0010] where, each independently,

[0011] A is absent or is a C₁-C₈-alkylene radical and

[0012] B is absent or is oxygen, sulphur or NR²

[0013] where R² is hydrogen or C₁-C₈-alkyl and

[0014] D is a carbonyl group and

[0015] E is C₁-C₈-alkyl, C₁-C₈-alkoxy, NH(C₁-C₈-alkyl) orN(C₁-C₈-alkyl)₂ or is a cyclic amino radical having 4 to 12 carbon atomsand

[0016] n is an integer of 0 to 3-m and

[0017] R^(F) is fluorine, C₁-C₁₂-fluoroalkyl, —O(C₁-C₁₂-fluoroalkyl) or—S(C₁-C₁₂-fluoroalkyl) and

[0018] m is an integer of 1 to 3,

[0019] which is characterized in that

[0020] compounds of the formula (II)

[0021] where

[0022] R¹ and R^(F), and also n and m, are as defined above areconverted

[0023] in the presence of urotropin and

[0024] in the presence of acid

[0025] to compounds of the formula (I).

[0026] Within the scope of the invention, all of the radicaldefinitions, parameters and illustrations hereinabove and citedhereinbelow, specified in general or within preferred ranges i.e. theparticular areas and areas of preference, may be combined as desired.

DETAILED DESCRIPTION OF THE INVENTION

[0027] Alkyl, alkylene, alkoxy and alkenyl are in each caseindependently a straight-chain, cyclic, branched or unbranched alkyl,alkylene, alkoxy and alkenyl radical respectively. The same applies tothe nonaromatic moiety of an arylalkyl radical.

[0028] C₁-C₄-Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl and tert-butyl, C₁-C₈-alkyl is additionally, forexample, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,neopentyl, 1-ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-2-methylpropyl,n-heptyl and n-octyl, and C₁-C₁₂-alkyl is still further additionally,for example, adamantyl, n-nonyl, n-decyl and n-dodecyl.

[0029] C₁-C₈-Alkoxy is, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, sec-butoxy and tert-butoxy, n-pentoxy,1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, neopentoxy,1-ethylpropoxy, cyclohexoxy, cyclopentoxy, n-hexoxy and n-octoxy.

[0030] Fluoroalkyl is in each case independently a straight-chain,cyclic, branched or unbranched alkyl radical which is substituted by atleast one fluorine atom and optionally further by chlorine atoms and/orbromine atoms.

[0031] C₁-C₁₂-Polyfluoroalkyl is, for example, trifluoromethyl,chlorofluoromethyl, difluoromethyl, difluorochloromethyl,1,1,2,2-tetrafluoro-1-ethyl, 2-chloro-2,1,1-trifluoro-1-ethyl,2,2,2-trifluoroethyl, pentafluoroethyl,1,1-dichloro-2,2,2-trifluoroethyl, heptafluoroisopropyl,n-nonafluorobutyl, perfluorocyclopentyl, perfluorocyclohexyl andperfluorododecyl.

[0032] The preferred substitution patterns for compounds of the formulae(I) and (II) are defined hereinbelow:

[0033] R¹ is preferably in each case independently C₁-C₄-alkyl orchlorine, more preferably methyl.

[0034] n is preferably 0 or 1, more preferably 0.

[0035] R^(F) is preferably fluorine, C₁-C₄-fluoroalkyl,—O(C₁-C₄-fluoroalkyl) or —S(C₁-C₄-fluoroalkyl), more preferablytrifluoromethyl, trifluoromethylthio, trifluoromethoxy,chlorofluoromethyl, chlorofluoromethylthio, chlorofluoromethoxy,difluoromethoxy, difluoromethyl, difluoromethylthio, difluoromethoxy,difluorochloromethyl, difluorochloromethylthio, difluorochloromethoxy,1,1,2,2-tetrafluoro-1-ethyl, 1,1,2,2-tetrafluoro-1-ethylthio,1,1,2,2-tetrafluoro-1-ethoxy, 2-chloro-2,1,1-trifluoro-1-ethyl,2-chloro-2,1,1-trifluoro-1-ethylthio, 2-chloro-2,1,1-trifluoro-1-ethoxy,2,2,2-trifluoroethyl, 2,2,2-trifluoroethylthio, 2,2,2-trifluoroethoxy,pentafluoroethyl, pentafluoroethylthio, penta-fluoroethoxy,1,1-dichloro-2,2,2-trifluoroethyl,1,1-dichloro-2,2,2-tri-fluoroethylthio,1,1-dichloro-2,2,2-trifluoroethoxy, heptafluoroisopropyl,n-nonafluorobutyl, perfluorocyclopentyl, perfluorocyclohexyl andperfluorododecyl.

[0036] m, in the case that all R^(F) are fluorine, is an integer of 1 to3, otherwise one or two, preferably one.

[0037] The compounds of the formula (II) are converted in the presenceof urotropin and in the presence of acid to compounds of the formula(I).

[0038] The molar ratio of urotropin to compounds of the formula (II) maybe, for example, 1:1 to 10:1, preferably 1:1 to 5:land more preferably1.5:1 to 2.5:1.

[0039] The molar ratio of acid to compounds of the formula (II) may be,for example, 1:1 to 100: 1, preferably 3:1 to 10:1.

[0040] The acid used is preferably one which, based on an aqueousreference system and 25° C., has a pKa value of 3 or less.

[0041] Particularly preferred acids are perfluoroalkylcarboxylic acids,ortho-phosphoric acid and polyphosphoric acids, organic sulphonic acids,hydrochloric, hydrobromic or hydriodic acid optionally dissolved inacetic acid, hydrogen sulphates and sulphuric acid, and greaterpreference is given to hydrobromic acid in acetic acid, polyphorphoricacids, methanesulphonic acid and trifluoroacetic acid, and still greaterpreference to trifluoroacetic acid.

[0042] Optionally, organic solvents may also be added to the reactionmixture, as long as they are substantially inert under the specifiedreaction conditions.

[0043] Preference is given to carrying out the reaction in the acidused.

[0044] The reaction temperature may be, for example, 0° C. to 150° C.,preferably 30 to 150° C. and more preferably 70 to 110° C.

[0045] The reaction pressure may be, for example, 0.5 to 100 bar,although preference is given to ambient pressure.

[0046] The procedure for converting the compounds of the formula (II)is, for example, that the compounds of the formula (II) and the acid areinitially charged and the urotropin is subsequently added.

[0047] The compounds of the formula (I) can be worked up in a mannerknown per se by extraction and subsequent distillation or, in the caseof compounds of the formula (I) which are solid at 30° C., byrecrystallization.

[0048] The compounds of the formula (I) are likewise encompassed by theinvention. The statements made above apply similarly to the areas ofpreference.

[0049] Particularly preferred individual compounds of the formula (I)include:

[0050] 5-fluoro-2-hydroxy-3-methylbenzaldehyde,5,6-difluoro-2-hydroxy-3-methylbenzaldehyde and2-hydroxy-3-methyl-5-(trifluoromethoxy)benzaldehyde.

[0051] Preference is given, for example, to preparing compounds of theformula (I) with compounds of formula (II) obtained by convertingcompounds of the formula (III)

[0052] where

[0053] R¹, R^(F) and m each have the definition and areas of preferencespecified above and

[0054] n is an integer between 0 and 3-m,

[0055] a) in the presence of formaldehyde and

[0056] in the presence of secondary amines of the formula (IV)

HNR³R⁴  (IV)

[0057] where

[0058] R³ and R⁴ are each independently C₁-C₈-alkyl or NR³R⁴ as a wholeis a cyclic amino radical having a total of 4 to 12 carbon atoms,

[0059] to compounds of the formula (V)

[0060] where

[0061] R¹, R³, R⁴ and R^(F), and also n and m, each have the definitionand areas of preference specified above, and

[0062] b) reducing the compounds of the formula (V) to compounds of theformula (II).

[0063] As important intermediates, the compounds of the formula (II) arelikewise encompassed by the invention, with the exception of2-methyl-4-fluorophenol.

[0064] Particularly preferred individual compounds of the formula (II)include: 4-fluoro-2-methylphenol, 4,5-difluoro-2- methylphenol and 2-methyl-4-(trifluoromethoxy)phenol.

[0065] The statements made above apply similarly to the areas ofpreference.

[0066] As important intermediates, the compounds of the formula (V) areadditionally encompassed by the invention, with the exception of5-fluoro-2-hydroxy-N,N-dimethylbenzylamine. Particularly preferredindividual compounds of the formula (V) include:4,5-difluoro-2-hydroxy-N,N-dimethylbenzylamine,2-hydroxy-5-(trifluoromethoxy)-N,N-dimethylbenzylamine,6-hydroxy-2,3,4-trifluoro-N,N-dimethylbenzylamine and2-hydroxy-4-(trifluoromethyl)-N,N-dimethylbenzylamine. The statementsmade above apply similarly to the areas of preference.

[0067] In step a), the compounds of the formula (III) are converted inthe presence of formaldehyde and in the presence of secondary amines ofthe formula (IV) to compounds of the formula (V).

[0068] The molar ratio of formaldehyde to compounds of the formula (III)may, for example, be 0.8 to 10, preferably 1.0 to 10 and more preferably1.2 to 3.6.

[0069] The molar ratio of secondary amines of the formula (IV) tocompounds of the formula (III) may be, for example, 0.8 to 10,preferably 1.0 to 10 and more preferably 1.05 to 3.15.

[0070] Formaldehyde may be used, for example, as paraformaldehyde and/orin the form of an aqueous solution, preferably in the form of a 32 to40% by weight solution.

[0071] The secondary amines of the formula (IV) can be used, forexample, without solvents or, where possible, in the form of aqueoussolutions. Particular preference is given to using dimethylamine in theform of an aqueous solution.

[0072] The reaction temperature may be, for example, −40° C. to 120° C.,preferably −10 to 40° C. and more preferably −5 to 10° C.

[0073] The reaction pressure may be, for example, 0.5 to 100 bar,although preference is given to ambient pressure.

[0074] The reaction time may be 10 min to 72 hours, preferably 3 hoursto 24 hours.

[0075] An example of a possible procedure for the reaction is toinitially charge the compounds of the formula (III) and the secondaryamines of the formula (IV), and subsequently to add the formaldehyde.

[0076] The compounds of the formula (V) can be worked up in a mannerknown per se by extraction and subsequent distillation or, in the caseof compounds of the formula (V) which are solid at 30° C., byrecrystallization.

[0077] The reduction according to step b) may advantageously be carriedout in the presence of hydrogen and hydrogenation catalyst.

[0078] Preferred hydrogenation catalysts are, for example, metals ormetal compounds such as salts or complexes of nickel, palladium,platinum, cobalt, rhodium, iridium and ruthenium, although preference isgiven to metals such as nickel or palladium. Preference is given tousing metals in finely divided form, for example as Raney metal orapplied to a support material.

[0079] Particular preference is given to carrying out the reduction withhydrogen and Raney nickel and/or palladium on carbon.

[0080] The reduction may, for example, be carried out at a reactiontemperature of 20° C. to 200° C., preferably 50 to 180° C. and morepreferably 80 to 150° C.

[0081] The partial hydrogen pressure in the reduction may be, forexample, 0.1 to 180 bar, preferably 10 to 150 bar and more preferably 40to 120 bar.

[0082] Optionally and with preference, the reduction may be carried outin the presence of solvent, as long as it is substantially inert underthe selected reaction conditions.

[0083] Suitable solvents are, for example, aliphatic, alicyclic oraromatic, optionally halogenated hydrocarbons, for example benzine,benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleumether, hexane, cyclohexane, dichloromethane, chloroform or carbontetrachloride; ethers such as diethyl ether, diisopropyl ether, dioxane,tetrahydrofuran or ethylene glycol dimethyl or diethyl ether; alcohols,for example methanol, ethanol and isopropanol, carboxylic acids, forexample acetic acid, or mixtures of solvents.

[0084] The reaction time in the reduction may be 10 min to 200 hours,preferably 5 to 100 hours.

[0085] In a particularly preferred embodiment, the reduction is carriedout in the presence of palladium on activated carbon and in the presenceof acetic acid at a partial hydrogen pressure of 40 to 120 bar.

[0086] The compounds of the formulae (I) and (II) obtainable accordingto the invention are suitable in particular in a process for preparingactive ingredients, for example active ingredients for medicaments.Preferred active ingredients for medicaments are those which are usedfor treating cardiovascular diseases, such as described in WO-A01/19780.

[0087] A substantial advantage of the invention is that the compounds ofthe formulae (I) and (II) can be prepared in a simple manner fromreadily available reactants. Moreover, the compounds of the formulae (I)and (II) according to the invention constitute valuable startingmaterials for the preparation of active ingredients, especially formedicaments.

[0088] The invention is further described by the following illustrativebut non-limiting examples.

EXAMPLES Example 1 Preparation of5-fluoro-2-hydroxy-3-methylbenzaldehyde

[0089] 84 g of 4-fluoro-2-methylphenol are dissolved in 512 ml oftrifluoroacetic acid and admixed with 181 g of hexamethylenetetramine inportions. On completion of addition, the reaction solution is heated to100° C. for 5 hours. After cooling, first 80 ml of 50% sulphuric acidand then 480 ml of water are added dropwise, then the solution isstirred further at room temperature for 3 hours. The reaction solutionis extracted three times with dichloromethane. The combined extracts arewashed once with water and dried, and the solvent is distilled off underreduced pressure. The residue is extracted repeatedly with n-hexane, theextracts are combined and the solvent is distilled off under reducedpressure. The crude product is subsequently fractionally distilled. 25 g(25% of theory) of a bright yellow solid are obtained having a meltingpoint of 49-52° C. and a boiling point of 70-72° C. at 7 mbar.

[0090] The ¹H NMR spectrum contained the following characteristicabsorptions (CDCl₃, δ/ppm): 1.08 (s,1 H, OH); 9.83 (s, 1 H, CHO); 7.14,7.07 (2×dd, 2 H, H-4, H-6); 2.28 (s, 3 H, CH₃).

Example 2 Preparation of 5,6-difluoro-2-hydroxy-3-methylbenzaldehyde

[0091] 30 g of 4,5-difluoro-2-methylphenol are dissolved in 180 ml oftrifluoroacetic acid and admixed with 57.2 g of hexamethylenetetraminein portions. On completion of addition, the reaction solution is heatedto 97-100° C. for 4 hours. After cooling, first 60 ml of 50% sulphuricacid and then 300 ml of water are added dropwise, then the solution isstirred further at room temperature for 2 hours. The reaction solutionis extracted three times with methyl tert-butyl ether. The combinedextracts are washed once with water and dried, and the solvent isdistilled off under reduced pressure. The residue is extractedrepeatedly with n-hexane, the extracts are combined and the solvent isdistilled off under reduced pressure. 12.5 g (33% of theory) of a brightyellow solid are obtained having a melting point of 53-56° C.

[0092] The ¹H NMR spectrum contained the following characteristicabsorptions (CDCl₃, δ/ppm): 11.39 (bs, 1 H, OH); 10.24 (s, 1 H, CHO);7.23 (m, 1 H, H-4); 2.22 (s, 3 H, CH₃).

[0093] The following spectrum was obtained by means of GC-MS (EI, 70 eV,I/%): 172 (100, M⁺).

Example 3 Preparation of2-hydroxy-3-methyl-5-(trifluoromethoxy)benzaldehyde

[0094] 100 g of 2-methyl-4-(trifluoromethoxy)phenyl are dissolved in 600ml of tri-fluoroacetic acid and admixed with 144 g ofhexamethylenetetramine in portions. On completion of addition, thereaction solution is heated to 100° C. for 16 hours. After cooling,first 200 ml of 50% sulphuric acid and then 700 ml of water are addeddropwise, then the solution is stirred further at room temperature for 3hours. Extraction is effected three times using methyl tert-butyl etherand the combined organic phases are washed once with water and dried,and the solvent is distilled off under reduced pressure. The residue isextracted repeatedly with n-hexane, the extracts are combined and thesolvent is distilled off under reduced pressure. The product can befurther purified by distillation. 40 g (34% of theory) of a pale yellowliquid are obtained having a boiling point of 65-67° C. at 4 mbar.

[0095] The ¹H NMR spectrum contained the following characteristicabsorptions (DMSO-d6, δ/ppm): 11.03 (bs, 1 H, OH); 10.12 (s, 1 H, CHO);7.59, 7.48 (2×m, 2 H, H-4,H-6); 2.26 (s, 3 H, CH₃).

[0096] The following spectrum was obtained by GC-MS (EI, 70 eV, I/%):220 (100, M⁺).

Example 4 Preparation of 4,5-difluoro-2-hydroxy-N,N-dimethylbenzylamine

[0097] 400 g of 3,4-difluorophenol are initially charged in 408 ml of40% aqueous dimethylamine solution and cooled to 0° C. At 0-5° C., 276ml of 37% aqueous formaldehyde solution are added dropwise within 60min. The mixture is kept at 5-10° C. for 2 hours and subsequentlystirred at room temperature for 20 hours. The mixture is admixed with600 ml of water. The organic phase is removed, the aqueous phase isextracted twice with dichloromethane, the combined organic phases aredried and the solvent is distilled off under reduced pressure. The crudeproduct is subsequently fractionally distilled under reduced pressure.395 g (65% of theory) of a colourless liquid having a boiling point of93° C. at 16 mbar are obtained.

[0098] The ¹H NMR spectrum contained the following characteristicabsorptions (CDCl₃, δ/ppm): 11.32 (s, 1 H, OH); 7.77, 7.60 (2 m, 2 H,H-3, H-6); 3.57 (s, 2 H, CH₂); 2.32 (s, 6 H, N(CH₃)₂).

[0099] The following spectrum was obtained by GC-MS (EI, 70 eV, I/%):187 (100, M⁺); 143 (36, (M-N(CH₃)₂)⁺).

Example 5 Preparation of2-hydroxy-5-(trifluoromethoxy)-N,N-dimethylbenzylamine

[0100] 130 g of 4-trifluoromethoxyphenol are initially charged in 97 mlof 40% aqueous dimethylamine solution and cooled to 3° C. At 0-5° C., 66ml of 37% aqueous formaldehyde solution are added dropwise within 45min. The mixture is kept at 5-10° C. for a further 2 hours and issubsequently stirred at room temperature for 19 hours. It is cooledagain to 0° C., 4.9 ml of 40% aqueous dimethylamine solution are addedand 3.3 ml of 37% aqueous formaldehyde solution are subsequently addeddropwise. The mixture is stirred at room temperature for a further 3hours. The mixture is admixed with 100 ml of water. The organic phase isremoved, the aqueous phase is extracted twice with dichloromethane, thecombined organic phases are dried and the solvent is distilled off underreduced pressure. The crude product is subsequently fractionallydistilled under reduced pressure. 118 g (69% of theory) of a lightyellow liquid having a boiling point of 110-112° C. at 18 mbar wereobtained.

[0101] The ¹H NMR spectrum contained the following characteristicabsorptions (CDCl₃, δ/ppm): 11.08 (bs, 1 H, OH); 7.03 (dd, 1 H, J_(H4-H3)=8.9 Hz, J _(H-4-H6)=2.4 Hz, H-4); 6.84 (d, 1 H,J_(H-6, H-4)=2.3 Hz, H-6); 6.80 (d, 1 H, J_(H3-H4)=8.8 Hz, H-3); 3.62(s, 2 H, CH₂); 2.32 (s, 3 H, CH₃).

[0102] The following spectrum was obtained by means of GC-MS (EI, 70 eV,I/%): 235 (100, M⁺); 191 (19, (M-N(CH₃)₂)⁺).

Example 6 Preparation of6-hydroxy-2,3,4-trifluoro-N,N-dimethylbenzylamine

[0103] 400 g of 3,4,5-trifluorophenol are initially charged in 359 ml of40% aqueous dimethylamine solution and cooled to 0° C. At 0-5° C., 243ml of 37% aqueous formaldehyde solution are added dropwise within 90min. Subsequently, the mixture is stirred at room temperature for 20hours. The mixture is admixed with 600 ml of water and 500 ml ofdichloromethane. The organic phase is removed, the aqueous phase isextracted once with dichloromethane, the combined organic phases aredried and the solvent is distilled off under reduced pressure. The crudeproduct is taken up in 500 ml of water and adjusted to pH 1-2 withcooling in an ice bath using dilute hydrochloric acid. The acidicsolution is extracted once with dichloromethane and subsequentlyadjusted to pH 8-9 with cooling in an ice bath using dilute sodiumhydroxide solution. The alkaline reaction solution is extracted threetimes with dichloromethane, the combined organic phases are washed oncewith water and dried, and the solvent is removed under reduced pressure.The crude product is subsequently fractionally distilled under reducedpressure. 305 g (55% of theory) of a light yellow liquid having aboiling point of 96° C. at 10 mbar are obtained.

[0104] The ¹H NMR spectrum contained the following characteristicabsorptions (CDCl₃, δ/ppm): 11.70 (s, 1 H, OH); 6.41 (m, 1 H, H-5); 3.71(s, 2 H, CH₂); 2.37 (s, 6 H, N(CH₃)₂).

Example 7 Preparation of2-hydroxy-4-(trifluoromethyl)-N,N-dimethylbenzylamine

[0105] 195 g of 3-trifluoromethylphenol are initially charged in 160 mlof 40% aqueous dimethylamine solution and cooled to 15° C. At 155° C.,108 ml of 37% aqueous formaldehyde solution are added dropwise within 40min. Subsequently, the mixture is stirred at room temperature for 20hours. The mixture is cooled again to 15° C., admixed with 8 ml of 40%aqueous dimethylamine solution and 5.5 ml of 37% aqueous formaldehydesolution are added dropwise. Subsequently, the mixture is stirred atroom temperature for a further 4.5 hours. The mixture is cooled again to15° C. and admixed with 32 ml of 40% aqueous dimethylamine solution, and21 ml of 37% aqueous formaldehyde solution are added dropwise.Subsequently, stirring is continued at room temperature for 17 hours.The mixture is admixed with 150 ml of water. The organic phase isremoved, the aqueous phase is extracted twice with dichloromethane, thecombined organic phases are washed once with water and the solvent isdistilled off under reduced pressure. The crude product is taken up in250 ml of water and adjusted to pH 1-2 with cooling in an ice bath usingdilute hydrochloric acid. The acidic solution is extracted once withdichloromethane and subsequently adjusted to pH 11 with cooling in anice bath using dilute sodium hydroxide solution. The alkaline reactionsolution is extracted twice with dichloromethane,.the combined organicphases are washed once with water and dried, and the solvent isdistilled off under reduced pressure. The crude product is subsequentlyfractionally distilled under reduced pressure. 186 g (71% of theory) ofa light yellow liquid having a boiling point of 91° C. at 14 mbar areobtained.

[0106] The ¹H NMR spectrum contained the following characteristicabsorptions (CDCl₃, δ/ppm): 7.08-6.98 (m, 3 H, H-3, H-5, H-6); 3.67 (s,2 H, CH₂); 2.32 (s, 6 H, N(CH₃)₂).

Example 8 Preparation of 4,5-difluoro-2-methylphenol

[0107] 214 g of 4,5-difluoro-2-hydroxy-N,N-dimethylbenzylamine areinitially charged in 700 ml of acetic acid in an autoclave, admixed with50 g of palladium/activated carbon (5%) and heated with 70 bar ofhydrogen to 100° C. for 26 hours. The autoclave is cooled anddecompressed. The catalyst is filtered off and washed with acetic acid,and the filtrate is admixed with 3 000 ml of water. This aqueoussolution is extracted three times with methyl tert-butyl ether. Thecombined organic phases are washed once with water and dried, and thesolvent is distilled off under reduced pressure. The crude product isfractionally distilled under reduced pressure. The distillate can befurther purified by crystallization. 98 g (58% of theory) of acolourless solid are obtained having a melting point of 68-70° C. and aboiling point of 78-80° C. at 13 mbar.

[0108] The ¹H NMR spectrum contained the following characteristicabsorptions (CDCl₃, δ/ppm): 6.92, 6.62 (2 m, 2 H, H-3, H-6); 4.82 (s, 1H, OH); 2.19 (2, 3 H, CH₃).

[0109] The following spectrum was obtained by means of GC-MS (EI, 70 eV,I/%): 144 (100, M⁺); 126 (21, (M−F+H)⁺).

[0110] Although the invention has been described in detail in theforegoing for the purpose of illustration, it is to be understood thatsuch detail is solely for that purpose and that variations can be madetherein by those skilled in the art without departing from the spiritand scope of the invention except as it may be limited by the claims.

What is claimed is:
 1. Process for preparing compounds of the formula(I)

where R¹ is in each case independently C₁-C₁₂-alkyl, chlorine or bromineor a radical of the formulae (IIa) or (IIb) A-B-D-E   (IIa) A-E   (IIb)where, each independently, A is absent or is a C₁-C₈-alkylene radicaland B is absent or is oxygen, sulphur or NR² where R² is hydrogen orC₁-C₈-alkyl and D is a carbonyl group and E is C₁-C₈-alkyl,C₁-C₈-alkoxy, NH(C₁-C₈-alkyl) or N(C₁-C₈-alkyl)₂ or is a cyclic aminoradical having 4 to 12 carbon atoms and n is an integer of 0 to 3-m andR^(F) is fluorine, C₁-C₁₂-fluoroalkyl, —O(C₁-C₁₂-fluoroalkyl) or—S(C₁-C₁₂-fluoroalkyl) and m is an integer of 1 to 3, comprisingconverting compounds of the formula (II)

where R¹ and R^(F), and also n and m, are as defined above in thepresence of urotropin and in the presence of acid to compounds of theformula (I).
 2. Process according to claim 1, characterized in that R¹is in each case independently C₁-C₄-alkyl or chlorine.
 3. Processaccording to claim 1, characterized in that n is 0 or
 1. 4. Processaccording to claim 1, characterized in that R^(F) is fluorine,C₁-C₄-fluoroalkyl, —O(C₁-C₄-fluoroalkyl) or —S(C₁-C₄-fluoroalkyl). 5.Process according to claim 1, characterized in that the molar ratio ofurotropin to compounds of the formula (II) is 1:1 to 10:1.
 6. Processaccording to claim 1, characterized in that the molar ratio of acid tocompounds of the formula (II) is 1:1 to 100:1.
 7. Process according toclaim 1, characterized in that the acid used is one which, based on anaqueous reference system at 25° C., has a pK value of 3 or less. 8.Process according to claim 1, characterized in that the acids used areperfluoroalkylcarboxylic acids, ortho-phosphoric acid and polyphosphoricacids, organic sulphonic acids, hydrochloric, hydrobromic or hydriodicacid optionally dissolved in acetic acid, hydrogen sulphates orsulphuric acid.
 9. Process according to claim 1, characterized in thatthe compounds of the formula (II) are prepared by converting compoundsof the formula (III)

where R¹, R^(F) and m each have the definition specified above and n isan integer between 0 and 3-m, a) in the presence of formaldehyde and inthe presence of secondary amines of the formula (IV) HNR³R⁴   (IV) whereR³ and R⁴ are each independently C₁-C₈-alkyl or NR³R⁴ as a whole is acyclic amino radical having a total of 4 to 12 carbon atoms, intocompounds of the formula (V)

where R¹, R³, R⁴ and R^(F), and also n and m, each have the definitionspecified above, and b) reducing the compounds of the formula (V) tocompounds of the formula (II).
 10. Process according to claim 9,characterized in that the molar ratio in step a) of formaldehyde tocompounds of the formula (III) is 0.8 to
 10. 11. Process according toclaim 9, characterized in that the molar ratio in step a) of secondaryamines of the formula (IV) to compounds of the formula (III) is 0.8 to10.
 12. Process according to claim 9, characterized in that thereduction of step b) is carried out in the presence of hydrogen andhydrogenation catalysts.
 13. Process according to claim 12,characterized in that the hydrogenation catalyst used is a metal ormetal compound selected from the group consisting of a salt or complexof nickel, palladium, platinum, cobalt, rhodium, iridium and ruthenium.14. Process according to claim 12, characterized in that the reductionin step b) is effected at a reaction temperature of 20° C. to 200° C.and a partial hydrogen pressure of 0.1 to 180 bar.
 15. Compounds of theformula (I)

where R¹ is in each case independently C₁-C₁₂-alkyl, chlorine or bromineor a radical of the formulae (IIa) or (IIb) A-B-D-E   (IIa) A-E   (IIb)where, each independently, A is absent or is a C₁-C₈-alkylene radicaland B is absent or is oxygen, sulphur or NR² where R² is hydrogen orC₁-C₈-alkyl and D is a carbonyl group and E is C₁-C₈-alkyl,C₁-C₈-alkoxy, NH(C₁-C₈-alkyl) or N(C₁-C₈-alkyl)₂ or is a cyclic aminoradical having 4 to 12 carbon atoms and n is an integer of 0 to 3-m andR^(F) is fluorine, C₁-C₁₂-fluoroalkyl, —O(C₁-C₁₂-fluoroalkyl) or—S(C₁-C₁₂-fluoroalkyl) and m is an integer of 1 to
 3. 16. The compoundof formula (I) according to claim 15 selected from the group consistingof 5-fluoro-2-hydroxy-3-methylbenzaldehyde,5,6-difluoro-2-hydroxy-3-methylbenzaldehyde and2-hydroxy-3-methyl-5-(trifluoromethoxy)benzaldehyde.
 17. Compounds ofthe formula (II)

where R¹ is in each case independently C₁-C₁₂-alkyl, chlorine or bromineor a radical of the formulae (IIa) or (IIb) A-B-D-E   (IIa) A-E   (IIb)where, each independently, A is absent or is a C₁-C₈-alkylene radicaland B is absent or is oxygen, sulphur or NR² where R² is hydrogen orC₁-C₈-alkyl and D is a carbonyl group and E is C₁-C₈-alkyl,C₁-C₈-alkoxy, NH(C₁-C₈-alkyl) or N(C₁-C₈-alkyl)₂ or is a cyclic aminoradical having 4 to 12 carbon atoms and n is an integer of 0 to 3-m andR^(F) is fluorine, C₁-C₁₂-fluoroalkyl, —O(C₁-C₁₂-fluoroalkyl) or—S(C₁-C₁₂-fluoroalkyl) and m is an integer of 1 to 3, with the exceptionof 4-fluoro-2-methylphenol.
 18. The compound of formula (II) accordingto claim 17 selected from the group consisting of4-fluoro-2-methylphenol, 4,5-difluoro-2-methylphenol and 2-methyl-4-(trifluoromethoxy)phenol.
 19. Compounds of the formula (V)

where R¹ is in each case independently C₁-C₁₂-alkyl, chlorine or bromineor a radical of the formulae (IIa) or (IIb) A-B-D-E   (IIa) A-E   (IIb)where, each independently, A is absent or is a C₁-C₈-alkylene radicaland B is absent or is oxygen, sulphur or NR² where R² is hydrogen orC₁-C₈-alkyl and D is a carbonyl group and E is C₁-C₈-alkyl,C₁-C₈-alkoxy, NH(C₁-C₈-alkyl) or N(C₁-C₈-alkyl)₂ or is a cyclic aminoradical having 4 to 12 carbon atoms and n is an integer of 0 to 3-m andR^(F) is fluorine, C₁-C₁₂-fluoroalkyl, —O(C₁-C₁₂-fluoroalkyl) or—S(C₁-C₁₂-fluoroalkyl) and m is an integer of 1 to 3 and R³ and R⁴ areeach independently C₁-C₈-alkyl or NR³R⁴ as a whole is a cyclic aminoradical having a total of 4 to 12 carbon atoms, with the exception of5-fluoro-2-hydroxy-N,N-dimethylbenzylamine.
 20. The compounds of formula(V) according to claim 19 selected from the group consisting of4,5-difluoro-2-hydroxy-N,N-dimethyl-benzylamine,2-hydroxy-5-(trifluoromethoxy)-N,N-dimethyl-benzylamine,6-hydroxy-2,3,4-trifluoro-N, N-dimethylbenzylamine and2-hydroxy-4-(trifluoromethyl)-N,N-dimethylbenzylamine.
 21. A process forpreparing active ingredients for medicaments comprising providingcompounds according to claim
 15. 22. A process for treatingcardiovascular disorders and diseases comprising administeringmedicaments containing active ingredients based on compounds of claim 15to subjects in need thereof.